1. Technical Field of the Invention
The present invention relates to substituted sulphoxides, particularly to optical isomers of “prazole” compounds. The present invention is also directed to a process for preparing optical isomers of “prazole” compounds, and use thereof in manufacturing medicaments.
2. Description of Prior Art
In general, peptic ulcer, of which 90% is gastric ulcer or duodenal ulcer, is caused by the enhancement of gastric mucosa injury factors, such as gastric acids, Helicobacter pylori (Hp), pepsins, non-steroidal anti-inflammatory drugs (NSAIDs) and the like, and/or the reduction of gastric mucosa defense factors, such as gastric mucosal barriers, mucosal blood flow, prostaglandin, reepithlialization, secretion of dicarbonates and the like, in body.
Generally, the immediate causes of ulcer include abnormal eating habit, excessive drinking, mental strain and various stresses, Hp infection, and administration of NSAIDs. Usually, Hp infection contributes to the onset, severity, progress, obstinateness and early relapse of ulcer, and gastric acid plays an important role in the injury of gastric mucosa and aggravation of ulcer. Therefore, “inhibition of gastric acid” and “eradication of Hp” (for Hp positive patients) have become two important aspects for current clinic treatment of peptic ulcer.
Many compounds having benzimidazole structures, such as Omeprazole, can inhibit any stimulated acid secretion from gastric parietal cell, i.e. inhibit the last step of the delivery of gastric acid from gastric parietal cell to gastral cavity, and therefore are very effective for treating ulcer. Since the last step involves in the exchange and transport of H+ and K+ induced by an enzyme, called H+, K+ transporting ATPase, this class of compounds that can inhibit the activity of H+, K+/ATPase are known as proton pump inhibitors (PPIs). Besides Omeprazole, such compounds are now commercially available with generic names of Lansoprazole, Pantoprazole, Rabeprazole, and Esomeprazole (an optically pure Omeprazole marketed in 2001).
“Prazoles” (i.e. PPIs) can be used alone to treat various peptic ulcer, including multiple ulcer caused by gastrin, drug-induced ulcer caused by NSAIDs, and H2 receptor antagonist (such as Cimetidine and Ranitidine) resistant refractory ulcer. The recovery ratio of ulcer treated with “prazoles” is up to 80% in two weeks and up to 100% in four weeks, and the relapse ratio thereof is substantially reduced. For Hp positive patients, “prazoles” can be used in combination with two antibacterial agents, where PPIs can enhance the activity of the antibacterial agents, and as a result a clearance of over 90% of Hp may be achieved in two weeks. Currently, the triple therapeusis of PPIs and two antibacterial agents has become a primary treatment of Hp positive peptic ulcer. Besides peptic ulcer, PPIs can also be used to treat gastro-oesophageal reflux diseases (GORD), zollinger-ellison syndrome (ZES) and other diseases associated with excessive gastric acid.
Il-Yang Pharm. Co., Ltd., Korea has developed a novel PPI, i.e. racemic 5-(1H-pyrrol-1-yl)-2-[[(3-methyl-4-methoxy-2-pyridyl)-methyl]sulfinyl]-benzimidazole, which shows superior anti-ulcer effects as compared with Omeprazole in the treatment of GORD, gastric ulcer and duodenal ulcer (KR 179,401 and U.S. Pat. No. 5,703,097).
The benzimidazoles described above as anti-ulcer agents are substituted sulphoxides having a stereogenic centre at the sulphur atom and thus exist as two optical isomers, i.e. enantiomers. If there is another stereogenic centre in the molecule, these compounds can exist as pairs of enantiomers. Corresponding sulphides of such compounds which already contain a stereogenic centre are not pro-chiral compounds, but chiral compounds. However, the sulphur atom in these compounds does not have asymmetry and therefore they are referred to as pro-chiral sulphides in respect of this invention. There are a large number of publications including patents and patent applications disclosing processes for preparation of the single enatiomers of such benzimidazole like Omeprazole, Lansoprazole, Pantoprazole and Rabeprazole, such as SE 9,500,818, DE 4,035,455, WO 94/27988 and ZL98124029.1 (which are hereby incorporated by reference in their entirety). It has been demonstrated that optically pure levo-Omeprazole (i.e. Esomeprazole) shows improved physiological activity and pharmacokinetics, and lower toxicity in comparison with the racemate of Omeprazole (Lindberg. P.; Weidolf, L. U.S. Pat. No. 5,877,192, 1999).
Our study on 5-(1H-pyrrol-1-yl)-2-[[(3-methyl4-methoxy-2-pyridyl)-methyl] sulfinyl]-benzimidazole has demonstrated that both its levo-enantiomer and dextro-enantiomer are inhibitors of gastric acid more potent than its racemate. However, the synthesis of such levo-enantiomer and dextro-enantiomer has never been reported in the art. Accordingly, we have made great efforts to study on the process for synthesis of the single enantiomers of 5-(1H-pyrrol-1-yl)-2-[[(3-methyl4-methoxy-2-pyridyl)-methyl]sulfinyl]-benzimidazole, and their use in medicaments for treatment of peptic ulcer and other diseases associated with excessive gastric acid.
Chinese patent CN 1070489C, which is hereby incorporated by reference herein in its entirety, has disclosed a process for enantioselective synthesis of Omeprazole, comprising asymmetrically oxidizing the corresponding prochiral sulphide in organic solvents (preferably toluene and ethyl acetate) in the presence of an organic base, a hydroperoxide, and a chiral titanium complex, which can be prepared from a titanium compound and a chiral alcohol. However, this process is not suitable for the synthesis of an enantiomerically enriched form of 5-(1H-pyrrol-1-yl)-2-[[(3-methyl4-methoxy-2-pyridyl) -methyl]sulfinyl]-benzimidazole due to its lower enantioselectivity and poor yield.